Estrogens play an important major role in existing methods of hormonal contraception. For contraception estrogens are commonly used together with a progestogen, e.g. levonorgestrel, desogestrel, norethisterone, cyproterone acetate, dienogest. The estrogens are needed for inhibiting follicle maturation and ovulation, but in addition they replace the endogenous ovarian secretion of estradiol which is suppressed to a major extent by the administration of a hormonal contraceptive. This replacement is important for preventing estrogen deficiency and for maintaining an artificial menstrual cycle and other genital functions.
Endogenous and exogenous estrogens fulfil important central nervous and metabolic functions in the female organism: normal estrogen levels make a decisive contribution to a woman's well-being. Notwithstanding the widespread use of estrogens in hormonal contraceptives, there are still some unsolved problems. Known estrogens, in particular the biogenic estrogens (i.e. estrogens naturally occurring in the human body), show serious pharmacokinetic deficits. Biogenic estrogens such as estradiol, estrone, estrone sulphate, esters of estradiol and estriol become bioavailable only to a very low degree when taken orally. This degree may vary so much from person to person that general dosage recommendations cannot be given. Fast elimination of these estrogens from the blood is another related problem. For instance, for the main human biogenic estrogen 17β-estradiol the half-life is around 1 hour. As a result, between separate (daily) administration events, blood serum levels of such biogenic estrogens tend to fluctuate considerably. Thus, shortly after administration the serum concentration is usually several times higher than the optimum concentration. In addition, if the next administration event is delayed, serum concentrations will quickly decrease to a level where the estrogen is no longer physiologically active.
The most important synthetically altered estrogenic steroid is 17α-ethinyl estradiol (EE). This estrogen is dominant in oral hormonal contraception. Apart from EE, mestranol has been used in a few cases; mestranol is a “prodrug” that is metabolised to EE in the organism. When applied orally to humans, EE has a much better bioavailability than the biogenic estrogens mentioned above, but its oral bioavailability varies to a large extent from individual to individual. Several authors have pointed to this as well as to the fact that concentrations in the blood proved to be highly fluctuating after oral application of this substance.
In addition to pharmacokinetic problems, the known estrogens also show pharmacodynamic deficits. After resorption from the intestinal lumen, orally applied active ingredients enter the organism via the liver. This fact is of specific importance for estrogenic agents as the liver is a target organ for estrogens; oral intake of estrogens results in strong estrogenic effects in the liver. The secretion activity that is controlled by estrogens in the human liver includes increased synthesis of transport proteins CBG, SHBG, TBG, several factors that are important for the physiology of blood clotting, and lipoproteins. If biogenic estrogens are introduced to the female organism while avoiding passage through the liver (e.g. by transdermal application), the liver functions mentioned remain largely unchanged. Therapeutically equivalent doses of biogenic estrogens, when applied orally, result in clear responses of hepatic parameters, such as increase of SHBG, CBG, angiotensinogen and HDL (high density lipoprotein). These hepatic effects of estrogens are also observed when equine estrogen formulations (so-called conjugated estrogens) are used. Ethinyl estradiol and diethylstilbestrol (DES) have an even greater hepatic estrogenicity. Elger et al., J. Steroid Biochem. Molec. Biol. (1995), 55(3/4), 395-403, have reported that EE or DES have much higher hepato-cellular than systemic estrogenicity: in relation to FSH-secretion inhibitory activity these estrogens are 4-18 times more active in the liver than estrone sulfate.
The aforementioned deficits are of considerable clinical significance when commonly known biogenic and synthetic estrogens are applied. Consequently, there is an as yet unmet need for estrogens that do not display these deficits and which can suitably be employed in oral contraceptive methods for females because of their ability to (a) reliably suppress follicle maturation and ovulation and to (b) effectively replace the endogenous ovarian secretion of estradiol.